Genotype-Phenotype Correlation in a Large Cohort of Eastern Sicilian Patients Affected by Phenylketonuria: Newborn...

Background: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to impaired amino acid metabolism. Early diagnosis through newborn screening (NBS) enables prompt treatment, preventing neurological complications. This study aims to describe the genetic and phenotypic spectrum of PKU and mild hyperphenylalaninemia (m-HPA) in patients diagnosed at the Department of Inborn Errors of Metabolism and Newborn Screening, Hospital G. Rodolico-S. Marco, Catania, over four decades (1987-2023). Materials and Methods: The retrospective analysis included 102 patients with elevated blood phenylalanine (Phe) levels born in Sicily and followed at the Institute. The phenotype evaluation comprised the Phe levels at birth/diagnosis, dietary tolerance, and sapropterin dihydrochloride responsiveness. The dietary compliance and Phe/Tyr ratios were assessed and compared across phenotypic classes and age groups. Results: Of 102 patients, 34 were classified as having classic PKU, 9 as having moderate PKU, 26 as having mild PKU, and 33 as having m-HPA, with a median age of 21.72 years. Common PAH variants included c.1066-11G>A (26/204 alleles), c.782G>A (18/204 alleles), and c.165delT (13/204 alleles). The phenotypes sometimes diverged from the genotype predictions, emphasizing dietary tolerance over the initial Phe levels for classification: m-HPA was statistically associated with a higher dietary tolerance (p < 0.001) compared to the classic, moderate, or mild forms of PKU. Conclusions: This study highlights the importance of large databases (e.g., BioPKU) for phenotype prediction and treatment optimization. Regular assessment of Phe/Tyr ratios is crucial for monitoring adherence and health. Phenotype determination, dietary management, and emerging therapies (Pegvaliase and gene therapy) are key to improving outcomes for PKU patients.